EP0190857B1

EP0190857B1 - Quinolone inotropic agents

Info

Publication number: EP0190857B1
Application number: EP86300524A
Authority: EP
Inventors: Simon Fraser Dr. Campbell; David Anthony Dr. Roberts
Original assignee: Pfizer Ltd; Pfizer Corp
Current assignee: Pfizer Ltd; Pfizer Corp
Priority date: 1985-01-30
Filing date: 1986-01-27
Publication date: 1990-03-21
Anticipated expiration: 2006-01-27
Also published as: AU557667B2; EP0190857A2; ES557430A0; FI860424A0; ATE51224T1; DK43286A; HUT40421A; JPS61176568A; EP0190857A3; GR860249B; AU5279886A; DK43286D0; CA1255662A; US4728654A; GB8502267D0; IE860258L; ES551343A0; PT81921A; CN85104392A; HU194831B

Abstract

Quinolone inotropic agents (and their pharmaceutically acceptable salts) of the formula:- <CHEM> where n is 0, 1 or 2; R<1> is selected from -NR<4>R<5>, -NR<4>CO(C1-C4 alkyl), -NR<4>CONR<4>R<5>, - NR<4>COOR<5>, S(O)m(C1-C4 alkyl), -SO2NR<4>R<5>, -NR<4>SO2R<5>, -OCONR<4>R<5>, -OCO(C1-C4 alkyl), -OR<5>, -OCH2.Het, -COOR<4>, -CONR<4>R<5> and Het min ; R<4> is H or C1-C4 alkyl and R<5> is H, C2-C4 alkyl or -CH2CH2N(C1-C2 alkyl)2, or R<4> and R<5> taken together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered heterocyclic group optionally containing a further heteroatom or group selected from O, S and N-R<6> where R<6> is H or C1-C4 alkyl; m is 0, 1 or 2; Het is a 5- or 6-membered nitrogen-containing aromatic heterocyclic group attached by a carbon atom to the adjacent -CH2- group; Het min is a 5- or 6-membered nitrogen-containing heterocyclic group; R<2>, which is attached to the 3-, 4-, 5-, 6-, 7- or 8-position, is H, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, cyano, halo, CF3 or -NR<4>R<5> where R<4> and R<5> are as defined above; R<3> is H or C1-C4 alkyl; X is H, C1-C4 alkoxy, hydroxy, halo or CF3; and the dotted line between the 3- and 4-positions represents an optional bond; and the pharmaceutically acceptable salts of the compounds of the formula (I).

Description

This invention relates to substituted quinolone cardiac stimulants which in general selectively increase the force of myocardial contraction without producing significant increases in the heart rate. The compounds are useful in the curative or prophylactic treatment of cardiac conditions, in particular in the treatment of heart failure.
EP-A-148623 discloses certain quinolone compounds as inotropic agents.
According to the present invention there are provided compounds having the general formula:-
or a pharmaceutically acceptable salt thereof, where R² is H or CH₃, and R' is -S(O)m(C₁-C₄ alkyl) where m is 0, 1 or 2, -S0₂NH₂, ―SO₂NH(C₁―C₄ alkyl), -OH, -COOH, ―COO(C₁―C₄ alkyl), -CONH₂, ―CON(C₁―C₄ alkyl)₂, imidazol-1-yl, -OCH₂(4-pyridyl), ―OCH₂CH₂N(C₁ or C₂ alkyl)₂, ―CON(C₁―C₄ alkyl)CH₂CH₂N(C₁ or C₂ alkyl)₂, or ―OCONH(C₁―C₄ alkyl), R' being attached to the 2¹- or 4¹-position of the benzene ring.
Although the compounds of the formula (I) are written as 2-(1H)-quinolones, it should be realised that the following tautomerism can occur.
However, as the keto-form is considered the more stable tautomer, the end products herein will be named and illustrated as quinolones although those skilled in the art will realise that both tautomers may be present or that any particular compound so named may exist predominantly as the hydroxy tautomer and the following disclosure is to be interpreted to incorporate all tautomeric forms.
The group R¹ is preferably in the ortho or para position in the benzene ring, and is most preferably αara.
Preferably, R¹ is ―S(O)_mCH₃ where m is 0, 1 or 2, -S0₂NH₂, -S0₂NHCH₃, -S0₂N(CH₃)₂, -NH₂, -OCH₃, -OH, -COOH, ―COOCH₃, ―CONH₂, -CON(CH₃)₂, imidazol-1-yl, -OCH₂(4-pyridyl), ―OCH₂CH₂N(CH₃)₂, ―CON(CH₃)CH₂CH₂N(CH₃)₂ or ―OCONH(n-propyl) where R² = CH₃.
In the present application, the most preferred individual compounds of the formula (I) have the formula:-
where R¹ is as defined for formula (I) and is preferably ―SOCH₃,―OH or ―CONH₂.
The most preferred individual compounds have the formula (IB) where R¹ is ―CONH₂ or ―SOCH₃.
The pharmaceutically acceptable salts of the compounds of the formulae (I) are either acid addition salts formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, methanesulphonate and p-toluenesulphonate salts, or are alkali metal or alkaline earth metal salts, particularly the sodium and potassium salts. When R' is, for example, carboxy and R⁶ is H then salt formation is of course possible at two sites in the molecule, e.g.:-
The cardiac stimulant activity of the compounds of the formula (I) is shown by their effectiveness in one or more of the following tests: (a) increasing the force of contraction in the "Starling" dog heart-lung preparation measured via a left ventricular catheter; (b) increasing myocardial contractility (left ventricular dp/dt max.) in the anaesthetised dog measured via a left ventricular catheter; (c) increasing myocardial contractility in the conscious dog with an implanted left ventricular transducer (dp/dt max.) or an exteriorised carotid artery loop (systolic time intervals).
In test (a), the positive inotropic effect of the test compound following bolus administration is measured in the "Starling" dog heart-lung preparation. The selectivity for increase in force versus frequency of contraction of the test compound is obtained.
In test (b), the positive inotropic action of the test compound following intravenous administration is measured in the anaesthetised dog. The magnitude and duration of this action, and the selectivity for increase in force versus frequency of contraction of the test compound are obtained, as are the peripheral effects, e.g. the effect on blood pressure.
In test (c) the positive inotropic action of the test compound following intravenous or oral administration to a conscious dog with an implanted left ventricular transducer (dp/dt max.) or an exteriorised carotid artery loop (systolic time intervals) is measured. The magnitude of the inotropic action, the selectivity for increase in force versus frequency of contraction, and the duration of action of the inotropic effect of the test compound are all obtained.
The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough salts or glucose to make the solution isotonic.
For administration to man in the curative or prophylactic treatment of cardiac conditions such as congestive heart failure, it is expected that oral dosages of the compounds of the invention will be in the range from 10 mg to 1 g daily, taken in 2 to 4 divided doses per day, for an average adult patient (70 kg). Dosages for intravenous administration would be expected to be within the range 0.5 to 100 mg per single dose as required, for example in the treatment of acute heart failure. Thus for a typical adult patient, individual tablets or capsules might contain 2.5 to 250 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Variations may occur depending on the weight and condition of the subject being treated as will be known to medical practitioners.
Thus the present invention provides a pharmaceutical composition comprising a compound of the formula (I) as defined above or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
The invention also provides a method of stimulating the heart of an animal, including a human being, which comprises administering to the animal a compound of formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined above, in an amount sufficient to stimulate the heart of the animal.
The invention yet further provides a compound of the formula (I) or pharmaceutically acceptable salt thereof, for use in medicine, in particular for use in stimulating the heart of a human being suffering from congestive heart failure.
The compounds of the formula (1) can be prepared by a number of routes, including the following:-

Route A:

This route can be illustrated in general terms as follows:-
R¹, R², X, n and the dotted line are as defined for formula (I). The demethylation is preferably carried out by heating the methoxyquinoline (II) either in aqueous mineral acid, typically in aqueous HCI or HBr and preferably in 48% HBr or 5 or 6M HCI, or in ethanol containing a catalytic quantity (generally 5-15% by volume) of 48% aqueous HBr, at up to reflux temperature for 0.5-8 hours. The product can then be isolated and purified by conventional procedures.
In cases where R' is an alkoxycarbonyl group (e.g. -COOCH₃), the demethylation may convert this to -COOH, in which case the carboxyl group can be re-esterified conventionally using, e.g., methanol in sulphuric acid.
Typical reactions are illustrated as follows:-
The novel starting materials of the formula (II) can be prepared by conventional procedures. These compounds form a part of the present invention.
In general terms these intermediates can be obtained as follows:-
In both cases, the reactants are typically heated at up to the reflux temperature in a suitable organic solvent such as tetrahydrofuran for, typically, 1-48 hours. The intermediates can then be isolated and if necessary purified by conventional techniques. For further experimental details see the relevant Preparations. The aryl or heteroaryl zinc chlorides can be conventionally obtained by the reaction of the corresponding bromo compound with n- or t-butyllithium and then with anhydrous zinc chloride. Tetrahydrofuran is a suitable solvent for these reactions, which should be carried out at low temperature.
Typical examples of the preparation of these intermediates are as follows:-

Route B

Compounds in which there is a hydroxy substituent on the phenyl ring can be prepared by the demethylation of the corresponding C_l-C₄ alkoxy compounds using conventional demethylation reagents such as aqueous mineral acid (preferably 48% aqueous HBr), boron tribromide or pyridinium hydrobromide. It is preferable to use aqueous mineral acid at up to reflux temperature.
When aqueous mineral acid is used, then this method can be essentially combined in one step with Route A, e.g. in the following manner:-
Route C
This route can be illustrated in general terms as follows:
"Hal" is Br or I. Thus it will be seen that the reaction involves the displacement of the leaving group "Hal" by the aryl zinc chloride with tetrakis (triphenylphosphine)palladium (O) catalysis. The reaction is typically carried out by heating the reactants at up to reflux temperature in a suitable organic solvent, e.g. THF.
A typical reaction is illustrated as follows:
Aryl magnesium chlorides can also be used in place of zinc chlorides using other suitable transition metal catalysts (e.g. nickel based).
The starting materials are either known compounds or are obtainable conventionally.
The aryl zinc chlorides are most conveniently obtained in situ by reacting the appropriate halo benzene derivative at from -70° to 0°C in THF with n-butyl or t-butyl lithium to obtain the lithio-derivative, followed by reaction of the lithio derivative with a solution of anhydrous zinc chloride in THF. The aryl zinc chlorides can also be prepared from the corresponding Grignard reagents by reaction with a solution of zinc chloride in THF. The desired end product can then be obtained by allowing the reaction mixture to warm to room temperature, followed by adding the appropriate halo-quinolone and the tetrakis (triphenylphosphine) palladium(O) in THF and then heating under reflux until the reaction is complete (e.g. in 1 to 48 hours). The product can then be recovered and purified conventionally.
The halo-quinolone starting materials of this route can also be prepared by conventional procedures. Typical routes to these materials, many of which are illustrated in detail in the following Preparations, are as follows:-

Route D

This route can be illustrated in general terms as follows:
where R⁷ is C₁-C₄ alkyl, ―CH₂CH₂N(C₁ or C₂ alkyl)₂ or HetCH₂-.
Thus the reaction involves alkylation of the phenolic hydroxyl group in the presence of triphenyl phosphine and diethylazodicarboxylate. The reaction is typically carried out in an inert organic solvent (e.g. THF) at up to the reflux temperature. The product can then be purified conventionally.
A typical reaction is illustrated as follows:

Route E

This route can be illustrated in general terms as follows:-

R⁴ is a C₁―C₄ alkyl group.

Thus the reaction involves conversion of the phenolic hydroxyl group to an N-alkylcarbamoyloxy group using a C₁-C₄ alkyl isocyanate. The reaction is typically carried out in a suitable organic solvent such as THF at up to reflux temperature. The products can then be purified conventionally.
A typical reaction is illustrated as follows:-
Route F
This route can be illustrated in general terms as follows:
The acid chlorides are typically obtained by alkaline hydrolysis of the corresponding C_l-C₄ alkyl esters followed by conversion of the resulting carboxylic acid salt (e.g. the sodium salt) to the acid chloride by treatment with thionyl chloride. Reaction of the crude acid chloride with ammonia or the appropriate amine then yields the desired end products which can be isolated and purified conventionally.
A tvnical reaction is illustrated as follows:-

Route G

Compounds in which m is 1 or 2 can be prepared by the oxidation of the corresponding compounds in which m is zero using the appropriate quantity of oxidizing agent. The preferred oxidising agents are peracid oxidising agents such as m-chloroperbenzoic acid.

Route H

Compounds having a single bond in the 3,4-position can be obtained by the hydrogenation of the corresponding compounds having a double bond in the 3,4-position according to conventional techniques, e.g. using H₂ over Pd/C. Typically the reaction is carried out in an organic solvent such as ethanol at 25-100°C and under 101-33667 kPa hydrogen pressure over palladised charcoal until the reaction is complete.

Route I

Compounds in which R³ is a C_l-C₄ alkyl group can be prepared by the N-alkylation of the corresponding compounds in which R³ is H, e.g. by reacting the quinolone starting material with sodium hydride or other strong base to form the anion, followed by reaction with a C₁―C₄ alkyl halide or di(C_l-C₄ alkyl)sulphate in a conventional manner.
Salts of the compounds of the formula (I) are preparable by entirely conventional methods, e.g. by reacting a solution of the compound (I) in an organic solvent with a solution of an appropriate acid in an organic solvent to form an acid addition salt, or by reacting the compound (I) with an appropriate base, e.g. an alkali metal or alkaline earth metal hydroxide, preferably aqueous sodium hydroxide, to form a pharmaceutically acceptable metal salt.
Where the compounds of the invention contain one or more asymmetric centres, then the invention includes the separated enantiomers and diastereoisomers or mixtures thereof. The separated forms can be obtained by conventional means.
The following Examples illustrate the preparation of the compounds (I). (All temperatures are in °C):-

Example 1

Preparation of 8-methyl-6-[4-methylsulphinylphenyl]-2-(1 H)-quinolone

A solution of 2-methoxy-8-methyl-6-[4-methylsulphinylphenyl]-quinoline (0.86 g) in 5M hydrochloric acid (10 cm³) was heated under reflux for 3.5 hours. The cooled mixture was partitioned between aqueous 2M sodium hydroxide solution (200 cm³) and chloroform:methanol, 19:1, (100 cm³), and the aqueous phase was further extracted with chloroform:methanol, 19:1 (5 x 50 cm³). The combined and dried (MgS0₄) organic extracts were evaporated in vacuo and the residue was recrystallised from ethyl acetate/ methanol to afford the title compound, m.p. 298-299°, (0.29 g).

Examples 2-12

The following compounds were prepared similarly to Example 1 starting from the appropriately substituted 2-methoxyquinoline and either 5M aqueous HCI (Examples 2-9), 6M aqueous HCI (Example 12) or 48% aqueous HBr (Examples 10 and 11).

Example 13

6-[4-Methoxycarbonylphenyl]2-(1H)-quinolone 1/4 hydrate and 6-(4-carboxyphenyl]-2-(1H)-quinolone disodium salt dihydrate

A suspension of 2-methoxy-6-[4-methoxycarbonylphenyl]-quinoline (6.71 g) in 5M HCI (150 cm³) was warmed at 100° for 6 hours. The cooled solution was filtered and dried to afford a solid (6.43 g). A small quantity (0.63 g) of this solid material was suspended in chloroform:methanol, 2:1 (5 cm³), and treated with 2M sodium hydroxide solution (2 cm³). After warming for 10 minutes at 100° the mixture was filtered and the filtrate was concentrated in vacuo to 2 cm³ volume to afford, on cooling, 6-[4-methoxycarbonylphenyl]-2-(1H)-quinolone 1/4 hydrate, m.p. >325°, (0.1 g).
The remainder of the solid material from Part A was heated under reflux in 5M sodium hydroxide (90 cm³) for 16 hours. The cooled solution was then filtered to give 6-[4-carboxyphenyl]-2-(1H)-quinolone disodium salt dihydrate, m.p. >300° (4.66 g).

Example 14

Part A

8-Methyl-6-[4-methoxycarbonylphenyl]-2-(1H)-quinolone.0.5 H₂0, m.p. 293°, was prepared similarly to Example 13(A) using 2-methoxy-8-methyl-6-(4-methoxycarbonylphenyl)quinoline and 5M HCI.

Part B

8-Methyl-6-[4-carboxyphenyl]-2-(1H)-quinolone disodium salt, 1.75 H₂O, mp. >300°, was prepared similarly to Example 13(B) by reacting a mixture of 8-methyl-6-(4-methoxycarbonylphenyl]-2-(1H)-quinolone and its 6-(4-carboxyphenyl) analogue with 5M sodium hydroxide.

Example 15

Preparation of 8-methyl-6-[4-hydroxyphenyl]-2-(1 H)-quinolone

A mixture of 2-methoxy-8-methyl-6-[4-methoxyphenyl]quinoline (4.82 g) and 48% aqueous HBr (100 cm³) was heated under reflux for 6 hours. The cooled mixture was diluted with water (200 cm³), the solid filtered off, and dissolved in chloroform:methanol, 4:1 (500 cm³). The organic phase was washed with water (2 x 25 cm³), dried (MgS0₄) and evaporated in vacuo to give a solid which was recrystallised from propan-2-ol to afford the title compound, m.p. 270-274°, (2.5 g).

Example 16

Preparation of 6-[4-methoxyphenyl]-2-(1H)-quinolone
A solution of t-butyl lithium (9.0 cm³ of a 2.0 M solution in n-pentane) was added at -70° to a stirred solution of 4-bromoanisole (1.13 cm³) in tetrahydrofuran (THF) (20 cm³) under nitrogen. After 10 minutes a solution of anhydrous zinc chloride (1.23 g) in THF (10 cm³) was added and the mixture was allowed to warm to room temperature over 0.5 hour. A mixture of 6-iodo-2-(lH)-quinolone (0.813 g) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) was added and the mixture was heated under reflux for 2 hours. Volatile material was then removed in vacuo and the residue was partitioned between chloroform:methanol, 9:1 (100 cm³), and a solution of ethylenediaminetetraacetic acid disodium salt (7 g) in water (100 cm³). The aqueous phase was further extracted with chloroform:methanol, 9:1 (3 x 100 cm³), and the combined and dried (MgS0₄) organic extracts were evaporated to give an oily solid which was triturated with ethyl acetate. Recrystallisation of the residue from ethyl acetate-methanol-chloroform afforded the title compound, m.p. 262―264° (0.359 g).

Example 17

Preparation of 8-methyl-6-[4-(4-pyridylmethoxy)phenyl]-2-(1 H)-quinolone
A solution of diethylazodicarboxylate (0.189 cm³) in THF (5 cm³) was added at room temperature to a stirred suspension of 8-methyl-6-[4-hydroxyphenyl]-2-(1H)-quinolone (0.25 g), 4-hydroxymethylpyridine (0.109 g) and triphenylphosphine (0.315 g) in THF (10 cm³) under nitrogen. The mixture was heated under reflux for 18 hours, silica (10 g) (Merck "MK 60.9385" [Trade Mark]) was added and volatile material was removed in vacuo. The residue was placed on top of a silica column (Merck "MK 60.9385" [Trade Mark]) and eluted with ethyl acetate:methanol, 9:1. Combination and evaporation of the appropriate fractions in vacuo gave a solid (0.24 g) which was recrystallised from ethyl acetate-methanol to afford the title compound, m.p. 270.5-273.5°, (0.08 g).

Example 18

8-Methyl-6-[4-(2-dimethylaminoethoxy)phenyl]-2-(1H)-quinolone, m.p. 216° (decomp.), was prepared similarly to the previous Example using 8-methyl-6-[4-hydroxyphenyl]-2-(lH)-quinolone, diethylazodicarboxylate, triphenylphosphine and 2-dimethylaminoethanol as the starting materials.

Example 19

Preparation of 8-methyl-6-[4-(N-n-propylcarbamoyloxy)phenyl]-2-(1H)-quinolone
A solution of 8-methyl-6-[4-hydroxyphenyl]-2-(1 H)-quinolone (0.30 g) and n-propylisocyanate (0.5 cm³) was heated under reflux in THF (10 cm³) under nitrogen for 50 hours. Methanol (10 cm³) was then added to disolve solid material, followed by silica (Merck "MK 60.9385" [Trade Mark]) (10 g), and the volatile material was removed in vacuo. The residue was placed on top of a silica column (Merck "MK 60.9385") and eluted with chloroform:methanol, 19:1. Combination and evaporation of appropriate fractions in vacuo gave a solid which was recrystallised from propan-2-ol to afford the title compound, m.p. 224_^228°, (0.28 g).

Example 20

Preparation of 6-[4-carbamoylphenyl]-2-(1H)-quinolone, 0.25 H₂0
A suspension of 6-[4-carboxyphenyl]-2-(1H)-quinolone disodium salt dihydrate (0.5 g) (see Example 13B) in thionyl chloride (10 cm³) was heated under reflux for 10 minutes. The cooled solution was evaporated in vacuo to afford a yellow solid which was treated without purification with aqueous ammonia solution (5 cm³, S.G. 0.88) with stirring. The solid material was filtered off and warmed with chloroform:methanol, 4:1, to remove soluble impurities and the remaining solid was filtered to afford the title compound, m.p. >320°, (0.3 g).

Examples 21-23

The following compounds were prepared similarly to the previous Example using 6-[4-carboxyphenyl]-2-(1H)-quinolone disodium salt dihydrate (Examples 21 and 22 or 8-methyl-6-[4-carboxyphenyl]-2-(1H)-quinolone disodium salt 1.75 hydrate (Example 23), and ammonia or the appropriately substituted amine as the starting materials:-
The following Preparations illustrate the synthesis of certain starting materials. All temperatures are in °C:

Preparation 1

2-Methoxy-6-[4-methoxycarbonylphenyl]quinoline
t-Butyllithium (30 cm³ of a 2.0 M solution in n-pentane) was added dropwise at -70° to a stirred solution of 6-bromo-2-methoxyquinoline (7.14 g) in tetrahydrofuran (THF) (50 cm³) under nitrogen. After 10 minutes a solution of anhydrous zinc chloride (4.09 g) in THF (30 cm³) was added and the solution was allowed to warm to room temperature. A mixture of methyl 4-iodobenzoate (7.8 g) and tetrakis (triphenylphosphine) palladium (0) (0.32 g) was added and the mixture was heated under reflux for 1 hour. Volatile material was removed in vacuo and the residue was partitioned between chloroform (150 cm³) and a solution of ethylenediaminetetraacetic acid disodium salt (22.4 g) in water (400 cm³). The aqueous phase was further extracted with chloroform (2 x 100 cm³), and the combined and dried (MgSO₄) organic extracts were evaporated to give a solid which was recrystallised from acetone to afford the title compound, m.p. 158-161°C, (6.81 g).

Preparations 2-10

The following compounds were prepared similarly to Preparation 1 using the appropriately substituted halobenzene derivative and either 6-bromo-2-methoxyquinoline (Preparations 2-5), or 6-bromo-8-methyl-2-methoxyquinoline (Preparations 6-10) as the starting materials.

Preparation 11

2-Methoxy-8-methyl-6-[4-methoxyphenyl]quinoline
n-Butyllithium (33.3 cm³ of a 1.5 M solution of n-hexane) was added dropwise at -70° to a stirred solution of 4-bromoanisole (6.26 cm³) in THF (70 cm³) under nitrogen. After ten minutes, a solution of anhydrous zinc chloride (6.814 g) in THF (50 cm³) was added and the mixture was allowed to warm to room temperature over 0.5 hour. A mixture of 6-bromo-2-methoxy-8-methylquinoline (12.8 g) and tetrakis (triphenylphosphine) palladium (0) (0.5 g) was added and the mixture heated under reflux for 2 hours. Volatile material was removed in vacuo and the residue was partitioned between chloroform (150 cm³) and a solution of ethylenediaminetetraacetic acid (40 g) in water (250 cm³). The organic layer was dried (MgS0₄) and evaporated to afford an oil which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with hexane:ethyl acetate, 19:1. Combination and evaporation of the appropriate fractions afforded the title compound (5.49 g). A small portion of this was recrystallised from methanol and had m.p. of 104_^106° and the following analysis:

Preparation 12

The following compound was prepared similarly to the previous Preparation using 6-bromo-2-methoxyquinoline and the appropriate phenyl zinc chloride derivative in the presence of tetrakis (triphenylphosphine) palladium (0):

Preparation 13

2-Methoxy-6-[4-methylsulphinylphenyl]quinoline
A solution of m-chloroperbenzoic acid (0.56 g) in dichloromethane (5 cm³) was added dropwise at -70° to a stirred solution of 2-methoxy-6-[4-methylthiophenyl]quinoline (0.7 g) in dichloromethane (10 cm³). The mixture was warmed to room temperature over 1 hour, taken into dichloromethane (25 cm³) and washed with sodium carbonate solution (10 cm³). The organic phase was dried (MgS0₄) and evaporated and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform: methanol, 19:1. The appropriate fractions were combined and evaporated to give a solid which was recrystallised from acetone-hexane to afford the title compound, m.p. 163.5-165.5°, (0.55 g).

Preparation 14

2-Methoxy-8-methyl-6-[4-methylsulphinylphenyl]quinoline, m.p. 119.5-121.5°C, was prepared similarly to the previous Preparation using 2-methoxy-8-methyl-6-[4-methylthiophenyl]quinoline and m-chloroperbenzoic acid as the starting materials.

Preparation 15

2-Methoxy-6-[4-methylsulphonylphenyl]quinoline
A solution of m-chloroperbenzoic acid (1.12 g) in dichloromethane (5 cm³) was added dropwise at -70⁰ to a stirred solution of 2-methoxy-6-[4-methylthiophenyl]quinoline (0.7 g) in dichloromethane (10 cm³). The mixture was allowed to warm to room temperature over one hour and the solution was washed with saturated sodium carbonate solution (10 cm³). The organic phase was dried (MgS0₄) and evaporated in vacuo to give a solid which was recrystallised from ethyl acetate to afford the title compound, m.p. 182-184° (0.674 g).

Preparation 16

6-Bromo-2-methoxyquinoline
A mixture of 6-bromo-2-[1H]-quinolone (2.90 g) and trimethyloxoniumtetrafluoroborate (2.10 g) was stirred in dichloromethane (50 cm³) for 48 hours under nitrogen. Aqueous 10% sodium hydroxide (20 cm³) was added and the aqueous phase was extracted with dichloromethane (2 x 40 cm³). The dried (MgS0₄) extracts were evaporated and the residue was crystallised from petroleum ether (b.p. 60-80°) to yield the title compound, m.p. 90-94°, (2.16 g).
6-Bromo-2-(1H)-quinoiine is a known compound.

Preparation 17

6-Bromo-2-methoxyquinoline (alternative to Preparation 16)
A solution of 2-chloro-6-bromoquinoline (4.0 g) in methanol (20 cm³) was heated under reflux with sodium methoxide [made from sodium (0.5 g) and methanol (20 cm³)] for 16 hours. The solvent was removed in vacuo and the residue was partitioned, between water (20 cm³) and chloroform (100 cm³). The aqueous phase was extracted with chloroform (2 x 30 cm³) and the dried (MgS0₄) organic extracts were evaporated to give a solid which was recrystallised from petroleum ether (b.p. 60―80°) to yield the title compound, m.p. 93-96°, (3.0 g).

Preparation 18

6-Bromo-2-methoxy-8-methylquinoline, m.p. 89-91°, was prepared similarly to the previous Preparation using 6-bromo-2-chloro-8-methylquinoline and sodium methoxide as the starting materials.
6-Bromo-2-chloroquinoline is a known compound.

Preparation 19

Trans-N-(4-Bromo-2-methylphenyl)-3-ethoxypropenamide
Trans-3-ethoxypropenoyl chloride (0.74 g) was added at 0° to a stirred solution of 4-bromo-2-methylaniline (0.93 g) in pyridine (10 cm³). After 0.5 hours water (40 cm³) was added, the solid material was filtered off, washed with water (30 cm³) and dried. The product was recrystallised from ethyl acetate to afford trans-N-(4-bromo-2-methylphenyl)-3-ethoxypropenamide, m.p. 163-164°, (1.3 g).

Preparation 20

Trans-N-(4-iodophenyl)-3-ethoxypropenamide, m.p. 181-182°, was prepared similarly to the previous Preparaton using trans-3-ethoxypropenoyl chloride and 4-iodoaniline as the starting materials.

Preparation 21

6-Bromo-8-methyl-2-(1H)-quinoline
Trans-N-(4-bromo-2-methylphenyl)-3-ethoxypropenamide (2.0 g) was added portionwise with stirring to 98% sulphuric acid (15 cm³) at room temperature. After 16 hours the solution was poured onto ice (100 cm³) and the resulting precipitate was filtered off and dried (1.5 g). Recrystallisation from ethyl acetate-methanol afforded 6-bromo-8-methyl-2-(1H)-quinoline, m.p. 272-274°.

Preparation 22

6-lodo-2-(lH)-quinolone, m.p. 260-263°, was prepared similarly to the previous Preparation using trans--N-(4-iodophenyl)-3-ethoxypropenamide and 98% sulphuric acid as the starting materials.

Preparation 23

6-Bromo-2-chloro-8-methylquinoline
A mixture of 6-bromo-8-methyl-2-(1H-quinoline (12.0 g) in phosphorus oxychloride (100 cm³) was heated under reflux for 2 hours. Volatile material was removed in vacuo, the residue dissolved in chloroform (200 cm³), and the resulting solution was poured onto ice (200 g). The mixture was basified with aqueous ammonia solution (S.G. 0.88) to pH 10 and the aqueous phase was further extracted with chloroform (2 x 100 cm³). The combined and dried (MgS0₄) extracts were concentrated in vacuo to give a solid (10.7 g) which was recrystallised from ethanol to afford 6-bromo-2-chloro-8-methyl-quinoline, m.p. 114-116°.

Claims

1. A process for preparing a compound of the formula:

or a pharmaceutically acceptable salt thereof, where R² is H or CH₃, and R¹ is ―S(O)_m(C₁―C₄ alkyl) where m is 0, 1 or 2, -S0₂NH₂, ―SO₂NH(C₁―C₄ alkyl), ―SO₂N(C₁―C₄ alkyl)₂, -NH₂, ―O(C₁―C₄ alkyl), -OH, -COOH, ―COO(C₁―C₄ alkyl), -CONH₂, ―CON(C₁-C₄ alkyl)₂, imidazol-1-yl, -OCH₂(pyridyl), ―OCH₂CH₂N(C₁ or C₂ alkyl)₂, ―CON(C₁―C₄ alkyl)CH₂CH₂N(C₁ or C₂ alkyl)₂, or ―OCONH(C₁―C₄ alkyl), R¹ being attached to the 2'- or 4'- position of the benzene ring, characterised by demethylating a compound of the formula:

where R¹ and R² are as defined above, said process being followed by, optionally, one or more of the following steps:

(a) conversion of a compound of the formula (IA) in which R¹ is hydroxy into a compound in which R¹ is -OCONH(C₁―C₄ alkyl) by reaction with an isocyanate of the formula (C₁―C₄ alkyl)NCO;

(b) conversion of a compound of the formula (IA) in which m is 0 into a compound in which m is 1 or 2 by oxidation;

(c) conversion of a compound of the formula (IA) in which R¹ is -COOH (or a salt thereof) into the corresponding acid chloride, followed by reaction of said acid chloride with a compound of the formula R⁴R⁵NH where R⁴ is H or C₁―C₄ alkyl and R⁵ is H, C₁―C₄ alkyl or ―CH₂CH₂N(C₁―C₂ alkyl)₂ so as to form a compound of the formula (I) in which R¹ is -CONR⁴R⁵;

(d) conversion of a compound of the formula (IA) in which R¹ is ―COO(C₁―C₄ alkyl) into a compound in which R¹ is -COOH by hydrolysis;

(e) conversion of a compound of the formula (IA) in which R¹ is -OH into a compound of the formula (IA) in which R¹ is ―OR⁷ where R⁷ is C₁―C₄ alkyl, ―CH₂CH₂N(C₁ or C₂ alkyl), or ―CH₂(pyridyl) by reaction with a compound of the formula R⁷OH in the presence of triphenylphosphine and diethylazodicarboxylate;

(f) conversion of a compound of the formula (IA) into a pharmaceutically acceptable salt.

2. A process according to claim 1, characterised in that the demethylation is either carried out with an aqueous mineral acid, or in ethanol containing a catalytic quantity of aqueous HBr.

3. A process according to claim 2, characterised in that the aqueous mineral acid is aqueous HCI or aqueous HBr.

4. A process according to claim 3, characterised in that the mineral acid is 48% aqueous HBr or 5 or 6M aqueous HCI, and wherein the reaction is carried out at up to the reflux temperature of the reaction mixture.

5. A process for preparing a compound of the formula (IA) as defined in claim 1, or a pharmaceutically acceptable salt thereof, characterised by reacting a compound of the formula:

where R² is H or CH₃ and Hal is Br or I, with a compound of the formula:

wherein R¹ is as defined in claim 1, and in the presence of Pd(PPh₃)₄; said process being followed by, optionally, one or more of steps (a) to (g) as defined in claim 1.

6. A process according to any preceding claim, characterised in that R¹ is ―S(O)_mCH₃ where m is 0, 1 or ₂, ―SO₂NH₂, ―SO₂NHCH₃ ―SO₂N(CH₃)₂, -_NH2, ―OCH₃, -_OH, -_COOH, _-COOCH3, -CONH₂, -CON(CH₃)₂, imidazol-1-yl, -OCH₂(4-pyridyl), ―OCH₂CH₂N(CH₃)₂, ―CON(CH₃)CH₂CH₂N(CH₃)₂, or -OCONH(n-propyl) where R² = CH₃.

7. A process according to any preceding claim, characterised in that R¹ is attached to the 4-position of the benzene ring.

8. A process according to claim 7, characterised in that a compound of the formula (IB) is prepared:

where R¹ is -SOCH₃, -OH or -CONH₂.

9. A process for preparing a pharmaceutical composition, characterised by mixing a compound of the formula (lA) is defined in claim 1, or a pharmaceutically acceptable salt therof, with a pharmaceutically acceptable diluent or carrier.

10. A compound of formula (IA) as defined in claim 1, or a pharmaceutically acceptable salt thereof.